One of the most commonly followed strategies in the therapy of neoplastic pathologies foresees the use of several drugs (chemotherapy) belonging to different classes and all acting by induction of the natural process of apoptosis in the tumoral cell.
Nevertheless, it is known that the tumor cells may respond in an unexpected manner to the drug therapy, showing, instead, a strong resistance to the same. It is also known that one of the main reasons for the drug resistance shown by the tumor cells is the incapacity of the cells to begin the process of apoptosis, in response to the chemotherapeutic agent.
A main reason for this, especially when using drugs producing different kinds of DNA damage, is the functional alteration (mutation or deletion) of the gene p53, which is no longer capable of initiating the process of cellular apoptosis in response to DNA damage, thus leading the cells to resist the drug action. The drug resistance levels of the tumor cells can be very high. For example, in the case of tumor cells of the colon-rectum in advanced phase, a therapy based on the antimetabolite and DNA-damaging drug 5-fluorouracil (5FU) shows an effective response only for 10-15% of the cells, and a combination of 5FU with new drugs such as irinotecan and oxaliplatin leads to an increase of the cell mortality up to 40-50%, a value which is still entirely unsatisfactory for an effective therapeutic action towards the neoplastic pathologies.
In recent years, a cell phenomenon was discovered called “RNA interference” (RNAi) by means of which gene expression is silenced in a specific manner. By taking advantage of such process, it is possible to obtain the selective silencing of genes with unknown function, thus permitting the definition of its specific function through the study of the obtained phenotype. By applying RNAi techniques and studying the phenotypic results, it is moreover possible to assign new functions to already known genes.
The genes involved in the phenomenon of drug resistance of the tumor cells are today largely unknown.
There is very much a need, therefore, to identify new genes involved in drug-resistance and to design methods and compounds capable of substantially diminishing the tumor cells' resistance to drugs.